VACCINE DRUG DELIVERY SYSTEMS

VACCINE DELIVERY
BY
NADIKATLAANUSHA
M.Pharm

CONTENTS
1. Vaccines introduction.
2. Cells of immune system.
3. Immunization.
4. Types of vaccines.
5. Evidence and mechanismof uptake and transport of antigens.
6. Deliverysystems used to promote uptake.
• Absorptionenhancers,
• Lipid carriers,
• Oral Immunization( oral polio vaccine),
• Controlled release microparticlesfor Vaccinedevelopment,
• Single dose Vaccine deliverysystemsusing Biodegradablepolymers.
3. Knowledgeof peptide based and nucleic acidbased vaccines.
ANUSHA NADIKATLA

VACCINE
A vaccine is a biological preparation that improves
immunity to a particular disease. A vaccine typically
contains an agent that resembles a disease causing
microorganism and is often made from weakened or
killed forms of the microbe, its toxins or one of its
surface proteins. The agent stimulates the body's
immune system to recognize foreign agents, destroy it,
and keep a record of it, so that the immune system can
more easily recognize and destroy any of these
microorganisms that it later encounters.
ANUSHA NADIKATLA

• The terms vaccine and vaccination are derived
from Variolae vaccinae (smallpox of the cow), the term
devised by Edward Jennner to denote cowpox.
• Vaccines can be prophylactic (example: to prevent or
ameliorate the effects of a future infection by any natural or
"wild" pathogen),or therapeutic (e.g., vaccines against
cancer are also being investigated; see cancer vaccine).
EFFECTIVENES
Vaccines do not guarantee complete protection from a
disease. This is because the host's immune system simply
does not respond adequately. This may be due to a lowered
immunity in general or because the host's immune system
does not have a B cell capable of generating antibodies to
that antigen.
ANUSHA NADIKATLA

CELLS OF IMMUNE SYSTEM
ANUSHA NADIKATLA

LYMPHOCYTES
Small white blood cells
which are responsible
for much of the work
of the immune system.
Lymphocytes can be
divided I n to 3 classes
• B-cells
• T-cells
• Natural killer cells
(NKC)
Mcell
L
L
L
L
L
L
M. cell
Plasma
cell
ANUSHA NADIKATLA

B & T CELLS
• T cells play a central role in cell- mediated immunity
while, B cells are lymphocytes that play a large role
in humoral immune response.
• B cell is an essential component of the adaptive
immune system
• B cells spend their entire life in the bone marrow
while the T-cells leave the bone marrow at an early
age and travel to the thymus, where they mature.
• The principal function of B cells is to make
antibodies against antigens, perform the role of
antigen presenting cells (APC) and eventually
develop in to memory B cells after activation by
antigen interaction. ANUSHA NADIKATLA

• On the other hand, T-cells constitute 60 - 75% of
blood lymphocytes.
• They can be distinguished from other lymphocytes
by the presence of a T cell receptor (TCR) on the cell
surface.
• Another key feature of B cells and T cells, includes
the receptors it has in its surface.
• T cells recognize a linear sequence of amino acids
where as, B cells the spatial arrangement of proteins,
nucleic acids, polysaccharides or lipids.
ANUSHA NADIKATLA

 HELPER T CELLS
They assist other white blood cells in immunologic
processes, including maturation of B cells in to plasma cells
and memory B cells, and activation of cytotoxic T cells and
macrophages.
 CYTOTOXIC T CELLS
They destroy virally infected cells and tumor cells and are
also implicated in transplant rejection.
 REGULATORY T CELLS
They are formally known as suppressor T cell and are
crucial for the maintenance of immunological tolerance.
 MEMORY T CELLS
These are a subset of antigen specific T cells that resist
long term after an infection has resolved. ANUSHA NADIKATLA

NATURAL KILLER CELLS
• They comprise about 10-50% of the lymphocytes of
circulating blood.
• The role of NK cells is analogous to that of cytotoxic
T cells in the vertebrate adaptive immune system.
ANTIGEN PRESENTING CELL
• Cells which do not have antigen specific receptors.
Instead they capture and progress antigens, present
them to T-cell receptors.
• These cells include Macrophages, B-cells and
Dendritic cells.
ANUSHA NADIKATLA

• Immunization, or immunisation, is the process by which
an individual's immune system becomes fortified against
an agent (known as the immunogen).
• When this system is exposed to molecules that are
foreign to the body, called non-self, it will orchestrate an
immune response, and it will also develop the ability to
quickly respond to a subsequent encounter because
of immunological memory. This is a function of
the adaptive immune system.
• Therefore, by exposing an animal to an immunogen in a
controlled way, its body can learn to protect itself this is
called active immunization.
ANUSHA NADIKATLA

• Active immunization/vaccination has been named one of
the “Ten Great Public Health Achievements” in the 20th
Century.
• Artificial active immunization is where the microbe, or
parts of it, are injected into the person before they are
able to take it in naturally. If whole microbes are used,
they are pre-treated.
• Their effectiveness depends on ability to replicate and
elicits a response similar to natural infection. It is
usually effective with a single dose. Example : Polio
vaccine.
ANUSHA NADIKATLA

• Passive immunization is when these elements are introduced
directly into the body, instead of when the body itself has to
make these elements.
• Currently, antibodies can be used for passive immunization.
This method of immunization begins to work very quickly,
but it is short lasting, because the antibodies are naturally
broken down, and if there are no B cells to produce more
antibodies, they will disappear.
• Passive immunization occurs physiologically, when
antibodies are transferred from mother to fetus
during pregnancy, to protect the fetus before and shortly
after birth.
• Artificial passive immunization is normally administered
by injection and is used if there has been a recent outbreak
of a particular disease or as an emergency treatment for
toxicity, as in for tetanus. ANUSHA NADIKATLA

• Immunization is done through various techniques, most
commonly vaccination.
• Vaccines against microorganisms that cause diseases can
prepare the body's immune system, thus helping to fight
or prevent an infection.
• Example in experimental vaccines against nicotine
(NicVAX) or the hormone ghrelin in experiments to
create an obesity vaccine.
• Before the introduction of vaccines, the only way people
became immune to an infectious disease was by actually
getting the disease and surviving it. Smallpox (variola)
was prevented in this way by inoculation, which
produced a milder effect than the natural disease.
ANUSHA NADIKATLA

TYPES OF VACCINES
ANUSHA NADIKATLA

 KILLED
Some vaccines contain killed, but previously virulent, micro-
organisms that have been destroyed with chemicals, heat,
radioactivity, or antibiotics. Examples
are influenza, cholera, bubonic plague, polio, hepatitis A,
and rabies.
 ATTENUATED
Some vaccines contain live, attenuated microorganisms.
Many of these are active viruses that have been cultivated
under conditions that disable their virulent properties, or
that use closely related but less dangerous organisms to
produce a broad immune response.
Although most attenuated vaccines are viral, some are
bacterial in nature. Examples include the viral
diseases yellow fever, measles, rubella, and mumps, and the
bacterial disease typhoid. ANUSHA NADIKATLA

 TOXOID
Toxoid vaccines are made from inactivated toxic compounds
that cause illness rather than the micro-organism.
Examples : Tetanus and diphtheria.
Not all toxoids are for micro-organisms; for
example, Crotalus atrox toxoid is used to vaccinate dogs
against rattlesnake bites.
 SUBUNIT
Protein subunit – rather than introducing an inactivated
or attenuated micro-organism to an immune system
(which would constitute a "whole-agent" vaccine), a
fragment of it can create an immune response.
Examples include the subunit vaccine against
• Hepatitis B virus that is composed of only the surface
proteins of the virus, the virus-like particle (VLP)ANUSHA NADIKATLA

• vaccine against human papillomavirus (HPV) that is
composed of the viral major capsid protein, and the
hemagglutinin and neuraminidase subunits of
the influenza virus.
• Subunit vaccine is being used for plague immunization.
 CONJUGATE
Conjugate – certain bacteria have polysaccharide outer coats
that are poorly immunogenic. By linking these outer coats to
proteins (e.g., toxins), the immune system can be led to
recognize the polysaccharide as if it were a protein antigen.
This approach is used in the Haemophilus influenzae type B
vaccine.
 RECOMBINANT VECTOR
By combining the physiology of one micro-organism and
the DNA of the other, immunity can be created against
diseases that have complex infection processes.ANUSHA NADIKATLA

 DNA VACCINATION
In recent years a new type of vaccine called DNA vaccination,
created from an infectious agent's DNA, has been developed.
• It works by insertion of viral or bacterial DNA into human
or animal cells.
• Some cells of the immune system that recognize the proteins
expressed will mount an attack against these proteins and
cells expressing them.
• Because these cells live for a very long time, if the pathogen
that normally expresses these proteins is encountered at a
later time, they will be attacked instantly by the immune
system.
 DENDRITIC CELL VACCINES
Combine dendritic cells with antigens in order to present the
antigens to the body's white blood cells, thus stimulating an
immune reaction.
ANUSHA NADIKATLA

EVIDENCE AND
MECHANISM OF UPTAKE
&
TRANSPORT OF ANTIGENS
ANUSHA NADIKATLA

(Gram +ve bacterium)
ANUSHA NADIKATLA

MECHANISMS OF ANTIGEN UPTAKE
There is growing evidence that different antigen-
presenting cells use specialized mechanisms for antigen
uptake. Macropinocytosis and the activity of the mannose
receptor have been identified as efficient mechanisms of
antigen capture in dendritic cells. The mechanism of
uptake determines the intracellular compartment to which
antigen is delivered and may determine the type of T-cell
epitopes generated. New pathways for presentation of
exogenous antigens on MHC class I and II molecules have
been identified. These findings provide new insights into
antigen presentation in vivo and will be instrumental in
designing better methods of vaccination.ANUSHA NADIKATLA

TRANSPORT OF ANTIGENS
• Transporter associated with antigen
processing (TAP) is a member of the ATP-binding-
cassette transporter family.It delivers cytosolic
peptides into the endoplasmic reticulum(ER), where
they bind to nascent MHC class I molecules.
• The TAP structure is formed of two proteins: TAP-
1 and TAP-2, which have one hydrophobic region
and one ATP-binding region each. They assemble
into a hetero dimer, which results in a four-domain
transporter.
ANUSHA NADIKATLA

PEPTIDE TRANSPORT
• TAP-mediated peptide transport is a multistep process. The
peptide-binding pocket is formed by TAP-1 and TAP-2.
• Association with TAP is an ATP-independent event, ‘in a fast
bimolecular association step, peptide binds to TAP, followed by a
slow isomerisation of the TAP complex’. It is suggested that the
conformational change in structure triggers ATP hydrolysis and
so initiates peptide transport.
• Both nucleotide-binding domains (NBDs) are required for peptide
translocation, as each NBD cannot hydrolyze ATP alone. The
exact mechanism of transport is not known; however, findings
indicate that ATP binding to TAP-1 is the initial step in the
transport process, and that ATP bound to TAP-1 induces ATP
binding in TAP-2.
• It has also been shown that unlocking of the loaded MHC class I
is linked to the transport cycle of TAP caused by signals from theANUSHA NADIKATLA

DELIVERY SYSTEMS USED
TO PROMOTE UPTAKE
ANUSHA NADIKATLA

ABSORPTION ENHANCERS
• Absorption enhancement is the technology aimed at
enabling non-injection delivery of poorly membrane-
permeable compounds.
• The term absorption enhancer usually refers to an agent
whose function is to increase absorption by enhancing
membrane permeation, rather than increasing solubility,
so such agents are sometimes more specifically termed as
permeation enhancers.
• Absorption enhancers are functional excipients included
in formulations to improve the absorption of a
pharmacologically active drug.
ANUSHA NADIKATLA

LIPOSOMAL DELIVERY SYSTEMS
• Liposomes are composed of phospholipid bilayers capable of
entrapping hydrophilic moieties in the aqueous
compartment and hydrophobic moieties in the lipid bilayers
with cholesterol imparting rigidity to the bilayer.
• Viruses, proteins, glycoproteins, nucleic acids,
carbohydrates, and lipids can be entrapped and targeted at
cellular and subcellular level for evoking immune responses.
• As vaccine adjuvants these systems exert
immunomodulatory effects by virtue of their particulate
nature and their ability to bind with cell surface lipid
receptors such as CD1a .
ANUSHA NADIKATLA

• There are many methods of preparation of liposome
liposome vaccine formulations for entrapment of
antigenic peptides and antigen encoding plasmid
DNAs.
• Liposomes are versatile and robust delivery systems for
systems for induction of antibody and T lymphocyte
lymphocyte responses to associated subunit antigens.
antigens.
• Liposomal vaccines based on viral membrane proteins
(virosomes) have been approved as products in Europe for
hepatitis A and influenza
ANUSHA NADIKATLA

ORAL IMMUNIZATION
POLIO VACCINE
ANUSHA NADIKATLA

• Poliomyelitis (polio) is a serious infectious disease caused
by a virus.
• Oral polio vaccine (OPV) is a live-attenuated vaccine,
produced by the passage of the virus through non-
human cells at a sub-physiological temperature, which
produces spontaneous mutations in the viral genome.
• In 1961, type 1 and 2 monovalent oral poliovirus vaccine
(MOPV) was licensed
• In 1962, type 3 MOPV was licensed.
• In 1963, trivalent OPV (TOPV) was licensed, and
became the vaccine of choice in the United States and
most other countries of the world, largely replacing the
inactivated polio vaccine.
• OPV is usually provided in vials containing 10-20 doses
of vaccine. ANUSHA NADIKATLA

• A single dose of oral polio vaccine (usually two drops)
contains 1,000,000 infectious units of Sabin 1 (effective
against PV1), 100,000 infectious units of the Sabin 2
strain, and 600,000 infectious units of Sabin 3.
• The vaccine contains small traces of antibiotics-
neomycin and streptomycin—but does not
contain preservatives.
• One dose of OPV produces immunity to all three
poliovirus serotypes in approximately 50% of recipients.
• Three doses of live-attenuated OPV produce protective
antibody to all three poliovirus types in more than 95%
of recipients
ANUSHA NADIKATLA

CONTROLLED RELEASE MICRO PARTICLES
FOR VACCINE DELIVERY
• PLGA(polylactide co-glycolic acid) is used as a
Biodegradable Microparticle for Vaccine Delivery due to
the abundance of data and information on its properties,
uses, and role in ongoing studies.
• A particularly interesting area is the use of
biodegradable microparticles to deliver DNA vaccines.
• DNA vaccines, or so called third generation vaccines,
“involve the deliberate introduction into tissues of a
DNA plasmid carrying an antigen-coding gene that
transfers cells in vivo and results in an immune
response”.
ANUSHA NADIKATLA

• Biodegradble microparticles, in particular, PLGA and
PLA, are good devices for DNA vaccine delivery
because the DNA is protected from enzymatic
degradation.
• Malaria is a mosquito-borne disease caused by a
parasite. People with malaria often experience fever,
chills, and flu-like illness. Left untreated, the disease
can be lethal.
• Annually, 350-500 million cases of malaria occur
worldwide.
ANUSHA NADIKATLA

• Rosas et al. effectively encapsulated a subunit malaria
antigen, SPf66, in PLGA-mixture microspheres and
demonstrated high antibody levels in mice and
monkeys.
• The purpose of their work was to provide a minimal
dose vaccine with a clinically relevant antigen, SPf66
(Phase III Trials), and the data propose that PLGA is a
promising vehicle for delivery.
• The microparticles (1.3 um average diameters) appear
smooth and spherical under electron microscopy .
Scanning electron microscopy of PLGA formulation.
ANUSHA NADIKATLA

SINGLE DOSE VACCINE DELIVERY SYSTEMS
USING BIODEGRADABLE POLYMERS
• Biodegradable polymers are defined as polymers
comprised of monomers linked to one another through
functional groups and have unstable links in the
backbone. Broken down into biologically acceptable
molecules that are metabolized and removed from the
body via normal metabolic pathways
• There are two types of biodegradable polymers.They
are : Natural biodegradable polymers eg : Albumin,
Collagen, Gelatin etc., Synthetic biodegradable
polymers eg : Aliphatic poly(esters), Polyanhydride ,
Polyphosphazene , Pseudo poly aminoacid , Poly(
orthoesters )etc.,
ANUSHA NADIKATLA

SINGLE DOSE VACCINE DELIVERY SYSTEMS
USING BIODEGRADABLE POLYMERS
ANUSHA NADIKATLA

BIODEGRADABLE POLYMERS AS ADJUVANTS
• we need adjuvants to increase the therapeutic efficiency
They form depot of antigen at the site of inoculation
with slow release of antigens. It can improves the
performance of vaccines by targeting the antigen to APC
.
• Biodegradable polymers such as poly( lactide -co-
glycolic acids) is most commonly used for vaccine
delivery. This polymers is mainly required for controlled
release of the drug from polymer matrix.
• Targeting to appropriate cell types to generate optimum
response. Development of formulation that can be used
as non-invasive.
ANUSHA NADIKATLA

SINGLE DOSE VACCINE DELIVERY USING
PREFILLED SYRINGES
• There are over 20 pharmaceutical companies
manufacturing prefilled syringes for at least 50
injectables drugs and vaccines.
Examples :
Heat stable vaccines,
Seasonal Influenza vaccine,
Polio vaccine etc.
• A prefilled syringe is a single dose packet of parenteral
drug to which a needle has been fixed.
• Prefilled syringes are ready to use disposable syringes
contains premeasured dosage, reduce dosing errors and
increase patient compliance.
ANUSHA NADIKATLA

KNOWLEDGE OF PEPTIDE
BASED VACCINES
ANUSHA NADIKATLA

• A peptide vaccine is a
type of subunit vaccine
in which a peptide of
the original pathogen is
used to immunize an
organism.
• These types of vaccines
are usually rapidly
degraded once injected
into the body, unless
they are bound to a
carrier molecule such
as a fusion protein.
ANUSHA NADIKATLA

The role of a therapeutic cancer vaccine essentially
involves activating the soldiers, namely
• Dendritic cells,
• Macrophages,
• Cytotoxic T cells and
• Natural killer cells to act against the tumor cells.
Dendritic cells and macrophages are the professional
antigen presenting cells (APCs) of the immune system.
In simple terms, they eat any foreign substance
encountered by them, and display antigens derived from it
onto their surface.
Such APCs then interact with and activate the helper and
cytotoxic T cells, as well as educate them to recognize the
cancerous cells.
ROLE OF A CANCER VACCINE
ANUSHA NADIKATLA

• The vast majority of published pre-clinical studies have
demonstrated the requirement of T-lymphocytes for the
eradication of solid tumors.
• Cytotoxic T-lymphocytes (CTLs) or CD8 + T cells,
represent the primary effector cells involved in tumor-
specific immune-mediated destruction of cancer cells.
Peptides are efficient tools for stimulation of antigen-
specific CD8 T cell.
• A variety of cancer associated antigens have been
identified, and are being studied for immune system
activation.
• They may be peptides present on the surface of cancer
cells, certain enzymes that aid a vital cancer-promoting
process, receptors for certain growth factors, etc.
ANUSHA NADIKATLA

• These antigens are classified as
Tumor-associated antigens (TAA) and
Tumor-specific antigens (TSA).
• The peptide vaccine thus prepared is injected into the
patient.
• The APCs(antigen-presenting cells) of the patient's
immune system engulf these peptides, and present them
on the surface in order to educate the other immune
cells.
• The educated immune cells, when encounter the same
antigen on a cancerous cell, bring about the destruction
of that cell.
ANUSHA NADIKATLA

KNOWLEDGE OF NUCLEIC ACID BASED VACCINES
• Effective use of ‘naked’ nucleic acids as vaccines would
undoubtedly be one of the most important advances in
the history of vaccinology. While nucleic acids show
much promise for use as vaccine vectors in experimental
animals, not a single naked nucleic acid vector has been
approved for use in humans.
• Nucleic acid vaccines have not been clearly
demonstrated to have any convincing efficacy in the
prevention or treatment of infectious diseases or cancer.
ANUSHA NADIKATLA

HOW DO NUCLEIC ACID VACCINES WORK?
• It has been a decade since workers found that injection
of ‘naked’ plasmid DNA, that is DNA without any
associated lipid, protein or carbohydrate, could elicit an
immune response.
• While the earliest studies were done using DNA, some
subsequent studies have explored the use of RNA
vaccines. Hence they are collectively referred as nucleic
acid vaccine.
• They are relatively simple to generate and safe to
administer. In contrast to vaccines that employ
recombinant bacteria or viruses, genetic vaccines consist
only of DNA or RNA, which is taken up and translated
into protein by host cells . ANUSHA NADIKATLA

• Unfortunately, immunization with naked nucleic acid is
relatively inefficient and virus vectors generally induce
far greater immune responses than DNA vaccines.
• A most recent improvement upon plasmid nucleic acid
vectors was the incorporation of alpha virus replicons.
‘Self-replicating’ or replicon-based genetic vaccines were
designed to overcome the poor efficacy of some current
DNA-based and RNA-based genetic vaccines.
• There are many DNA vaccines in clinical and pre-
clinical trials, including vaccines for HIV, herpes,
hepatitis and influenza .
ANUSHA NADIKATLA

• The DNA vaccine is composed of a plasmid DNA that
contains the genetic code for a TSA or TAA.
• When this DNA plasmid is injected into the skin or
muscle, it is engulfed and internalized by the
surrounding cells as well as APCs.
• Here, the genetic information is decoded, the peptide
antigen is synthesized and displayed onto the surface,
and cross-presented to the APCs.
• The APCs then educate other cells, and initiate an
immune response against the tumor cells.
• The efficiency of DNA vaccine can be increased by
addition of certain pathogenic sequences adjacent to the
antigen sequence or by use of modern delivery systems
like nanoparticles. ANUSHA NADIKATLA

HOW DNA VACCINE IS MADE
Viral gene
Expression
plasmid
Plasmid with foreign gene
Recombinant DNA
Technology
ANUSHA NADIKATLA

Bacterial cell
Transform into
bacterial cell
Plasmid
DNA
ANUSHA NADIKATLA

Plasmid DNA get
Amplified
ANUSHA NADIKATLA

Plasmid DNA
Purified
Ready to use
ANUSHA NADIKATLA

ADVANTAGES OF DNA VACCINES
• Elicit both humoral and cell mediated immunity.
• Focused on antigen of intrest.
• Long term immunity.
• Refrigeration is not required.
• Stable for storage.
DISADVANTAGES OF DNA VACCINES
• Limited to protein immunogen only.
• Extended immunostimmulation leads to chronic
inflamation.
• Some antigen require processing which some times
does not occur.
ANUSHA NADIKATLA

RISKS ASSOCIATED WITH VACCINES
Vaccines also have some sort of risks.
• The primary risk associated with vaccines,
especially vaccines that utilize live organisms, is
that the vaccine it self causesillness.
• Another risk is that the vaccine may behave as a
super antigen and over stimmulate the immune
system.
• Yet a third risk is that some individuals may have
an allergic reaction to the vaccine, especially
vaccines produced in embryonated chicken eggs
and in transgenic plants.
ANUSHA NADIKATLA

RECENT RESEARCH
• Approaches for designing a preventive HIV
vaccine.
• Vaccine against dengue.
• Liver cancer vaccine effective in mice.
• Vaccine for malignant brain tumors.
• Combined MMRV ( measles-mumps-rubella-
varicella ) vaccine : Rise in febrile seizures?
• Spanish Flu-Like virus with pandemic potential
ANUSHA NADIKATLA

CONCLUSION
• Vaccines are one of the most effective health interventions
ever developed.
• Although various vaccines have been succesfully developed
for several diseases, research is still in progress to develop
vaccines for life threatening diseases like cancer, AIDS etc.
• Understanding the mechanism of absorption enhancement
may be very useful toward registration. However, it seems
reasonable that once a delivery technology is proven to be
successful for one particular drug, that technology might be
readily adapted to improving the delivery of other poorly
absorbed drugs.
• As the vaccines have a lot of benefits, they do carry some
harmful effects too.
ANUSHA NADIKATLA

REFERENCES
1. Aungst BJ. Intestinal permeation enhancers. J Pharm
Sci. 2000;89:429–442. doi: 10.1002/(SICI)1520-
6017(200004)89:4<429::AID-JPS1>3.0.CO;2-J. [PubMed]
2. Swenson ES, Curatolo WJ. Intestinal permeability enhancement for
proteins, peptides and other polar drugs: mechanisms and potential
toxicity. Adv Drug Del Rev. 1992;8:39–92. doi: 10.1016/0169-
409X(92)90015-I
3. Hochman J, Artursson P. Mechanisms of absorption enhancement
and tight junction regulation. J Contr Rel.1994;29:253–267. doi:
10.1016/0168-3659(94)90072-8.
4. Fix JA. Strategies for delivery of peptides using absorption-
enhancing agents. J Pharm Sci. 1996;85:1282–1285. doi:
10.1021/js960158a. [PubMed]
5. Arbit E, Kidron M. Oral insulin: The rationale for this approach and
current developments. J Diabet Sci Technol. 2009;3:562–
567. [PMC free article] [PubMed]
ANUSHA NADIKATLA

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